The present invention is directed to a method for resolving a stereoisomer mixture of a compound containing an olefin moiety using a chiral ketone mediated kinetic resolution.
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, depend on the stereochemistry of a drug""s chiral center. In addition, properties of a polymer containing a chiral monomeric unit depend on the enantiomeric purity of the monomer.
Although there are many asymmetric chemical reactions which produce enantiomerically enriched products, the scope of these reactions are limited. Separation of a stereoisomeric mixture (e.g., racemic or geometric isomers; of a compound is often difficult and/or a time-consuming task. One method of separating (or enriching) a racemic mixture of a compound is to react the racemic mixture with a chiral compound to produce diastereoisomers which may be physically separated, e.g., by chromatography, distillation or crystallization.
Many enzymatic methods are also available for separating stereoisomers of compounds containing one or more hydroxy groups. In addition, a kinetic resolution method for allylic alcohols is also available. For example, enrichment of one particular stereoisomer in a racemic allylic alcohol mixture can be achieved by using titanium catalyzed asymmetric epoxidation to convert predominantly one of the allylic alcohol stereoisomer to an epoxide.
Despite the availability of these and other methods for resolving a stereoisomeric mixture of compounds, there is a need for a method for resolving a variety of stereoisomer mixtures of compounds containing at least one olefin moiety. There is also a need for a method for resolving a stereoisomer mixture of compounds which does not contain an allylic alcohol functional group.
Present invention provides a method for increasing a relative concentration of at least one stereoisomer of a compound having at least one olefinic moiety, from the stereoisomer mixture. The method generally involves converting one of the stereoisomers of the compound to an epoxide at a higher rate than the conversion of the other stereoisomer.
The method of the present invention involves contacting an oxidizing agent with a mixture of a chiral ketone and a stereoisomer mixture of the compound to epoxidize the olefinic moiety of the compound. Epoxidation of one stereoisomer of the compound occurs at a relatively higher rate than epoxidation of the other stereoisomer resulting in a relative increase in the concentration of the other stereoisomer.
The chiral ketone is selected from the group consisting of compounds of the formula: 
wherein
each of W, X, Y and Z is independently CR9R10, O, NR11, NR11R12, S, Se, Si or P;
each of l, m, n and p is independently an integer from 0 to 3;
each of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is independently hydrogen, halide, hydroxyl, nitro, thio, or alkyl, alkoxy, aryl, silyl, siloxy, carbonyl, carboxylate, ester, amino, sulfinyl, sulfonyl, sulfate, sulfite, phosphate or phosphite groups containing from 1 to about 20 carbon atoms, or two or more R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are linked to form (i.e., together forms) 3 to about 10 membered cyclic moiety containing 1 to about 20 carbon atoms; and
each of R11 and R12 is hydrogen, oxygen or alkyl, sulfonyl, alkoxy or carbonyl groups containing from 1 to about 20 carbon atoms, or R11 and R12 are linked to form (i.e., together forms) 3 to about 10 membered cyclic moiety containing 1 to about 20 carbon atoms.
Preferably a chiral ketone is selected from the group consisting of the compound of the formula: 
wherein preferably, m is 0, Y is O or CR9R10, n and p are 1, and Z is CR9R10.
Preferably two or more R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are linked to form 3 to about 10 membered cyclic moiety containing 1 to about 20 carbon atoms, more preferably R1 and R2 are linked to form a moiety of the formula: 
xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94. Alternatively, R1 and R7 are linked to form a moiety of the formula xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94, or xe2x80x94C(CH3)2xe2x80x94.
Preferably R3 and R6 are linked to form a moiety of the formula xe2x80x94Oxe2x80x94C(CH3)2Oxe2x80x94 or a moiety of the formula xe2x80x94Oxe2x80x94 C(CH2CH3)2Oxe2x80x94.
Preferably R4, R5, R9 and R10 are independently hydrogen, halide or alkoxy, carboxyl or alkyl groups having 1 to about 20 carbon atoms. More preferably, R4, R5 and R10 are hydrogen and R9 is hydrogen, halide, or alkoxy, carboxyl, sulfinyl or alkyl groups having 1 to about 20 carbon atoms.
Preferably the chiral ketone is derived from a carbohydrate, quinic acid or carvone. More preferably the ketone is derived from a group consisting of carvone, inositol, quinic acid, (D)-fructose, (L)-fructose, (D)-arabinose, (L)-arabinose and (L)-sorbose.
In a particular embodiment of the present invention, the chiral ketone is a compound of the formula: 
Preferably the oxidizing agent selected from the group consisting of peracids, hydrogen peroxide, sodium hypochlorite, potassium peroxomonosulfate, sodium perborate, tetrabutylammonium monopersulfate and hypofluoride (HOF). More preferably, the oxidizing agent is potassium peroxomonosulfate.
Preferably the pH of the mixture during the epoxidation reaction is from about pH 5 to about pH 14, more preferably from about pH 10 to about pH 14, and most preferably from about pH 10 to about pH 12.
The pH of the mixture is adjusted by adding a base. Useful bases include carbonates, bicarbonates, hydroxides, borates and phosphates. Preferably, the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium borate, sodium phosphate, potassium phosphate, potassium hydroxide, tetraalkylammonium hydroxide, and mixtures thereof.